tbuckley/cabot-search huggingface dataset:
Valproic acid increases CAR T cell cytotoxicity against acute myeloid leukemia
Authors: Jingjing Wen, Yanxin Chen, Jiajie Yang, Chunye Dai, Shenjie Yu, Wenting Zhong, Lilin Liu, Chengguanng He, Wenmin Zhang, Ting Yang, Lingfeng Liu, Jianda Hu
Journal: Journal for ImmunoTherapy of Cancer (2023)

The treatment of B cell malignancies has dramatically changed with the introduction of immunotherapy, especially chimeric antigen receptor T (CAR-T) cell therapy. However, only limited efficacy is observed in acute myeloid leukaemia (AML). In the study, We detected CD123 and CLL-1 expression on leukaemia cells from Relapsed/Refractory AML (R/R AML) patients. Then, we constructed anti-CD123 CAR and CLL-1 CAR with different co-stimulation domains (CD28 or 4-1BB) and detected their anti-AML effects. To increase the efficacy of CAR-T cell therapy, we tested different strategies, including application of combined checkpoint inhibitors and histone deacetylase inhibitors (HDACi) in vivo and in vitro We found CD123 and CLL-1 were highly expressed on AML cells. The proportions of T cell subsets and NK cells involved in anti-tumour or anti-inflammation processes in AML patients significantly decreased when compared with healthy donors. Both CD123 CAR and CLL-1 CAR displayed specific anti-AML effects in vitro To improve the lysis effects of CAR-T cells, we combined CAR-T cell therapy with different agents. PD-1/PD-L1 antibodies only slightly improved the potency of CAR-T cell therapy (CD123 CAR-T 60.92% ± 2.9087% vs. 65.43% ± 2.1893%, 60.92% ± 2.9087% vs. 67.43% ± 3.4973%; 37.37% ± 3.908% vs. 41.89% ± 5.1568%, 37.37% ± 3.908% vs. 42.84% ± 4.2635%). However, one HDACi (valproic acid [VPA]) significantly improved CAR-T cell potency against AML cells (CLL-1 CAR-T 34.97% ± 0.3051% vs. 88.167% ± 1.5327%, p < 0.0001; CD123 CAR-T 26.87% ± 2.7010% vs. 82.56% ± 3.086%, p < 0.0001 in MV411; CLL-1 CAR-T 78.77% ± 1.2061% vs. 93.743% ± 1.2333%, p < 0.0001; CD123 CAR-T 64.10% ± 1.5130% vs. 94.427% ± 0.142%, p = 0.0001 in THP-1). Combination therapy prolonged the overall survival of mice when compared with single CD123 CAR-T cell therapy (median survival: 180 days vs. unfollowed). A possible mechanism is that activated CD8+T cells upregulate natural-killer group 2 member D (NKG2D), and VPA upregulates NKG2D ligand expression in AML cells, contributing to NKG2D-mediated cytotoxicity of CAR-T cells against tumour cells. In conclusion, CD123 and CLL-1 are promising targets for AML CAR-T cell therapy. A combination of VPA pre-treatment and CAR-T against AML exhibits synergic effects.
Recent trends in asthma diagnosis, preschool wheeze diagnosis and asthma exacerbations in English children and adolescents: a SABINA Jr study
Authors: Constantinos Kallis, Ekaterina Maslova, Ann D Morgan, Ian Sinha, Graham Roberts, Ralf J P van der Valk, Jennifer K Quint, Trung N Tran
Journal: Thorax (2023)

Background Asthma-related burden remains poorly characterised in children in the UK. We quantified recent trends in asthma prevalence and burden in a UK population-based cohort (1‒17-year-olds). Methods The Clinical Practice Research Datalink Aurum database (2008‒2018) was used to assess annual asthma incidence and prevalence in 1‒17-year-olds and preschool wheeze in 1‒5-year-olds, stratified by sex and age. During the same period, annual asthma exacerbation rates were assessed in those with either a diagnosis of preschool wheeze or asthma. Results Annual asthma incidence rates decreased by 51% from 1403.4 (95% CI 1383.7 to 1423.2) in 2008 to 688.0 (95% CI 676.3 to 699.9) per 10 5 person-years (PYs) in 2018, with the most pronounced decrease observed in 1‒5-year olds (decreasing by 65%, from 2556.9 (95% CI 2509.8 to 2604.7) to 892.3 (95% CI 866.9 to 918.3) per 10 5 PYs). The corresponding decreases for the 6‒11- and 12‒17-year-olds were 36% (1139.9 (95% CI 1110.6 to 1169.7) to 739.9 (95% CI 720.5 to 759.8)) and 20% (572.3 (95% CI 550.4 to 594.9) to 459.5 (95% CI 442.9 to 476.4)) per 10 5 PYs, respectively. The incidence of preschool wheeze decreased over time and was slightly more pronounced in the 1‒3 year-olds than in the 4-year-olds. Prevalence of asthma and preschool wheeze also decreased over time, from 18.0% overall in 2008 to 10.2% in 2018 for asthma. Exacerbation rates increased over time from 1.33 (95% CI 1.31 to 1.35) per 10 PYs in 2008 to 1.81 (95% CI 1.78 to 1.83) per 10 PYs in 2018. Conclusion Paediatric asthma incidence decreased in the UK since 2008, particularly in 1–5-year-olds; this was accompanied by a decline in asthma prevalence. Preschool wheeze incidence also decreased in this age group. However, exacerbation rates have been increasing.
Intravenous versus super-selected intra-arterial chemotherapy in children with advanced unilateral retinoblastoma: an open-label, multicentre, randomised trial
Authors: Xuyang Wen, Jiayan Fan, Mei Jin, Hua Jiang, Jiakai Li, Minglei Han, Chengyue Zhang, Xiaoyu He, Yingxiu Luo, Jie Yang, Min Zhou, Jia Tan, Xinji Yang, Xunda Ji, Jing Zhang, Junyang Zhao, Renbing Jia, Xianqun Fan
Journal: The Lancet Child & Adolescent Health (2023)
Cost-effectiveness of endoscopic, surgical and pharmacological obesity therapies: a microsimulation and threshold analyses
Authors: Monica Saumoy, Devika Gandhi, Seth Buller, Shae Patel, Yecheskel Schneider, Gregory Cote, Michael L Kochman, Nikhil R Thiruvengadam, Reem Z Sharaiha
Journal: Gut (2023)

Objective Weight loss interventions to treat obesity include sleeve gastrectomy (SG), lifestyle intervention (LI), endoscopic sleeve gastroplasty (ESG) and semaglutide. We aimed to identify which treatments are cost-effective and identify requirements for semaglutide to be cost-effective. Design We developed a semi-Markov microsimulation model to compare the effectiveness of SG, ESG, semaglutide and LI for weight loss in 40 years old with class I/II/III obesity. Extensive one-way sensitivity and threshold analysis were performed to vary cost of treatment strategies and semaglutide adherence rate. Outcome measures were incremental cost-effectiveness ratios (ICERs), with a willingness-to-pay threshold of US$100 000/quality-adjusted life-year (QALY). Results When strategies were compared with each other, ESG was cost-effective in class I obesity (US$4105/QALY). SG was cost-effective in class II obesity (US$5883/QALY) and class III obesity (US$7821/QALY). In class I/II/III, obesity, SG and ESG were cost-effective compared with LI. However, semaglutide was not cost-effective compared with LI for class I/II/III obesity (ICER US$508 414/QALY, US$420 483/QALY and US$350 637/QALY). For semaglutide to be cost-effective compared with LI, it would have to cost less than US$7462 (class III), US$5847 (class II) or US$5149 (class I) annually. For semaglutide to be cost-effective when compared with ESG, it would have to cost less than US$1879 (class III), US$1204 (class II) or US$297 (class I) annually. Conclusions Cost-effective strategies were: ESG for class I obesity and SG for class II/III obesity. Semaglutide may be cost-effective with substantial cost reduction. Given potentially higher utilisation rates with pharmacotherapy, semaglutide may provide the largest reduction in obesity-related mortality.
TIPSS plus extrahepatic collateral embolisation may decrease variceal rebleeding and post-TIPSS hepatic encephalopathy
Authors: Lianhui Zhao, Qiong Wu, Qian Li, Anbang Chen, Yifu Xia, Xiubin Sun, Jidong Jia, Shan Shan, Guangchuan Wang, Chunqing Zhang
Journal: Gut (2023)
Deep-learning-enabled protein–protein interaction analysis for prediction of SARS-CoV-2 infectivity and variant evolution
Authors: Guangyu Wang, Xiaohong Liu, Kai Wang, Yuanxu Gao, Gen Li, Daniel T. Baptista-Hon, Xiaohong Helena Yang, Kanmin Xue, Wa Hou Tai, Zeyu Jiang, Linling Cheng, Manson Fok, Johnson Yiu-Nam Lau, Shengyong Yang, Ligong Lu, Ping Zhang, Kang Zhang
Journal: Nature Medicine (2023)
Telomere-to-telomere assemblies of 142 strains characterize the genome structural landscape in Saccharomyces cerevisiae
Authors: Samuel O’Donnell, Jia-Xing Yue, Omar Abou Saada, Nicolas Agier, Claudia Caradec, Thomas Cokelaer, Matteo De Chiara, Stéphane Delmas, Fabien Dutreux, Téo Fournier, Anne Friedrich, Etienne Kornobis, Jing Li, Zepu Miao, Lorenzo Tattini, Joseph Schacherer, Gianni Liti, Gilles Fischer
Journal: Nature Genetics (2023)

Pangenomes provide access to an accurate representation of the genetic diversity of species, both in terms of sequence polymorphisms and structural variants (SVs). Here we generated the Saccharomyces cerevisiae Reference Assembly Panel (ScRAP) comprising reference-quality genomes for 142 strains representing the species' phylogenetic and ecological diversity. The ScRAP includes phased haplotype assemblies for several heterozygous diploid and polyploid isolates. We identified circa (ca.) 4,800 nonredundant SVs that provide a broad view of the genomic diversity, including the dynamics of telomere length and transposable elements. We uncovered frequent cases of complex aneuploidies where large chromosomes underwent large deletions and translocations. We found that SVs can impact gene expression near the breakpoints and substantially contribute to gene repertoire evolution. We also discovered that horizontally acquired regions insert at chromosome ends and can generate new telomeres. Overall, the ScRAP demonstrates the benefit of a pangenome in understanding genome evolution at population scale.
Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma
Authors: Renáta Váraljai, Lisa Zimmer, Yahya Al-Matary, Paulien Kaptein, Lea J. Albrecht, Batool Shannan, Jan C. Brase, Daniel Gusenleitner, Teresa Amaral, Nina Wyss, Jochen Utikal, Lukas Flatz, Florian Rambow, Hans Christian Reinhardt, Jenny Dick, Daniel R. Engel, Susanne Horn, Selma Ugurel, Wiebke Sondermann, Elisabeth Livingstone, Antje Sucker, Annette Paschen, Fang Zhao, Jan M. Placke, Jasmin M. Klose, Wolfgang P. Fendler, Daniela S. Thommen, Iris Helfrich, Dirk Schadendorf, Alexander Roesch
Journal: Nature Cancer (2023)

Recent studies suggest that BRAFV600-mutated melanomas in particular respond to dual anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibition (ICI). Here we identified an over-representation of interleukin (IL)-17-type 17 helper T (TH17) gene expression signatures (GES) in BRAFV600-mutated tumors. Moreover, high baseline IL-17 GES consistently predicted clinical responses in dual-ICI-treated patient cohorts but not in mono anti-CTLA-4 or anti-PD-1 ICI cohorts. High IL-17 GES corresponded to tumor infiltration with T cells and neutrophils. Accordingly, high neutrophil infiltration correlated with clinical response specifically to dual ICI, and tumor-associated neutrophils also showed strong IL-17-TH17 pathway activity and T cell activation capacity. Both the blockade of IL-17A and the depletion of neutrophils impaired dual-ICI response and decreased T cell activation. Finally, high IL-17A levels in the blood of patients with melanoma indicated a higher global TH17 cytokine profile preceding clinical response to dual ICI but not to anti-PD-1 monotherapy, suggesting a future role as a biomarker for patient stratification.
SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response
Authors: Philip Bland, Harry Saville, Patty T. Wai, Lucinda Curnow, Gareth Muirhead, Jadwiga Nieminuszczy, Nivedita Ravindran, Marie Beatrix John, Somaieh Hedayat, Holly E. Barker, James Wright, Lu Yu, Ioanna Mavrommati, Abigail Read, Barrie Peck, Mark Allen, Patrycja Gazinska, Helen N. Pemberton, Aditi Gulati, Sarah Nash, Farzana Noor, Naomi Guppy, Ioannis Roxanis, Guy Pratt, Ceri Oldreive, Tatjana Stankovic, Samantha Barlow, Helen Kalirai, Sarah E. Coupland, Ronan Broderick, Samar Alsafadi, Alexandre Houy, Marc-Henri Stern, Stephen Pettit, Jyoti S. Choudhary, Syed Haider, Wojciech Niedzwiedz, Christopher J. Lord, Rachael Natrajan
Journal: Nature Genetics (2023)

Abstract SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant ( SF3B1 MUT ) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1 MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G 2 /M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1 MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population.
NF-κB subunits direct kinetically distinct transcriptional cascades in antigen receptor-activated B cells
Authors: Mingming Zhao, Prashant Chauhan, Cheryl A. Sherman, Amit Singh, Mary Kaileh, Krystyna Mazan-Mamczarz, Hongkai Ji, Jaimy Joy, Satabdi Nandi, Supriyo De, Yongqing Zhang, Jinshui Fan, Kevin G. Becker, Png Loke, Weiqiang Zhou, Ranjan Sen
Journal: Nature Immunology (2023)

Abstract The nuclear factor kappa B (NF-κB) family of transcription factors orchestrates signal-induced gene expression in diverse cell types. Cellular responses to NF-κB activation are regulated at the level of cell and signal specificity, as well as differential use of family members (subunit specificity). Here we used time-dependent multi-omics to investigate the selective functions of Rel and RelA, two closely related NF-κB proteins, in primary B lymphocytes activated via the B cell receptor. Despite large numbers of shared binding sites genome wide, Rel and RelA directed kinetically distinct cascades of gene expression in activated B cells. Single-cell RNA sequencing revealed marked heterogeneity of Rel- and RelA-specific responses, and sequential binding of these factors was not a major mechanism of protracted transcription. Moreover, nuclear co-expression of Rel and RelA led to functional antagonism between the factors. By rigorously identifying the target genes of each NF-κB subunit, these studies provide insights into exclusive functions of Rel and RelA in immunity and cancer.
Leaning into the digital age: the role of TikTok and other technologies in providing mental health information
Authors: Declan Grabb
Journal: BMJ (2023)

Clinicians can engage in public health education by creating their own content or partnering with reputable health organisations to disseminate accurate information.They can also guide patients on how to identify reliable sources of information and recognise potential misinformation.These actions could begin to help patients access accurate content and allow clinicians to spend less time countering misinformation.We as clinicians should be leading these conversations and ensuring access to reliable content, not simply criticising the various media patients use.
Covid-19: Leaked cremation data hint at true scale of China’s death rate
Authors: Owen Dyer
Journal: BMJ (2023)

Covid-19: Leaked cremation data hint at true scale of China's death rate Owen DyerCremation figures released and then quickly withdrawn by authorities in China's Zhejiang province appear to confirm widespread doubts about the government's official pandemic death count, and lend support to international forecasts which predicted roughly 1.5 million deaths from covid in the weeks after China abandoned its zero covid policy last December.
The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma
Authors: Kai Rejeski, Doris K. Hansen, Radhika Bansal, Pierre Sesques, Sikander Ailawadhi, Jennifer M. Logue, Eva Bräunlein, David M. Cordas dos Santos, Ciara L. Freeman, Melissa Alsina, Sebastian Theurich, Yucai Wang, Angela M. Krackhardt, Frederick L. Locke, Emmanuel Bachy, Michael D. Jain, Yi Lin, Marion Subklewe
Journal: Journal of Hematology & Oncology (2023)

Abstract Background BCMA-directed CAR T-cell therapy (CAR-T) has altered the treatment landscape of relapsed/refractory (r/r) multiple myeloma, but is hampered by unique side effects that can lengthen hospital stays and increase morbidity. Hematological toxicity (e.g. profound and prolonged cytopenias) represents the most common grade ≥ 3 toxicity and can predispose for severe infectious complications. Here, we examined the utility of the CAR-HEMATOTOX (HT) score to predict toxicity and survival outcomes in patients receiving standard-of-care idecabtagene vicleucel and ciltacabtagene autoleucel. Methods Data were retrospectively collected from 113 r/r multiple myeloma patients treated between April 2021 and July 2022 across six international CAR-T centers. The HT score—composed of factors related to hematopoietic reserve and baseline inflammatory state—was determined prior to lymphodepleting chemotherapy. Results At lymphodepletion, 63 patients were HT low (score 0–1) and 50 patients were HT high (score ≥ 2). Compared to their HT low counterparts, HT high patients displayed prolonged severe neutropenia (median 9 vs. 3 days, p &lt; 0.001), an increased severe infection rate (40% vs. 5%, p &lt; 0.001), and more severe ICANS (grade ≥ 3: 16% vs. 0%, p &lt; 0.001). One-year non-relapse mortality was higher in the HT high group (13% vs. 2%, p = 0.019) and was predominantly attributable to fatal infections. Response rates according to IMWG criteria were higher in HT low patients (≥ VGPR: 70% vs. 44%, p = 0.01). Conversely, HT high patients exhibited inferior progression-free (median 5 vs. 15 months, p &lt; 0.001) and overall survival (median 10.5 months vs. not reached, p &lt; 0.001). Conclusions These data highlight the prognostic utility of the CAR-HEMATOTOX score for both toxicity and treatment response in multiple myeloma patients receiving BCMA-directed CAR-T. The score may guide toxicity management (e.g. anti-infective prophylaxis, early G-CSF, stem cell boost) and help to identify suitable CAR-T candidates.
Genetic impacts on DNA methylation help elucidate regulatory genomic processes
Authors: Sergio Villicaña, Juan Castillo-Fernandez, Eilis Hannon, Colette Christiansen, Pei-Chien Tsai, Jane Maddock, Diana Kuh, Matthew Suderman, Christine Power, Caroline Relton, George Ploubidis, Andrew Wong, Rebecca Hardy, Alissa Goodman, Ken K. Ong, Jordana T. Bell
Journal: Genome biology (2023)

Pinpointing genetic impacts on DNA methylation can improve our understanding of pathways that underlie gene regulation and disease risk.
Comparison between measurable residual disease relapse and morphologic relapse in acute myeloid leukemia and high-grade myeloid neoplasms
Authors: Lauren Shih, Megan Othus, Kelda Schonhoff, Carole Shaw, Jacob Appelbaum, Anna B. Halpern, Pamela S. Becker, Roland B. Walter, Elihu Estey, Mary-Elizabeth Percival
Journal: Leukemia (2023)
Readmission following hospital admission for community-acquired pneumonia in England
Authors: Hannah Lawrence, Tricia M McKeever, Wei Shen Lim
Journal: Thorax (2023)

Introduction Readmission rates following hospital admission with community-acquired pneumonia (CAP) have increased in the UK over the past decade. The aim of this work was to describe the cohort of patients with emergency 30-day readmission following hospitalisation for CAP in England and explore the reasons for this. Methods A retrospective analysis of cases from the British Thoracic Society national adult CAP audit admitted to hospitals in England with CAP between 1 December 2018 and 31 January 2019 was performed. Cases were linked with corresponding patient level data from Hospital Episode statistics, providing data on the primary diagnosis treated during readmission and mortality. Analyses were performed describing the cohort of patients readmitted within 30 days, reasons for readmission and comparing those readmitted and primarily treated for pneumonia with other diagnoses. Results Of 8136 cases who survived an index admission with CAP, 1304 (15.7%) were readmitted as an emergency within 30 days of discharge. The main problems treated on readmission were pneumonia in 516 (39.6%) patients and other respiratory disorders in 284 (21.8%). Readmission with pneumonia compared with all other diagnoses was associated with significant inpatient mortality (15.9% vs 6.5%; aOR 2.76, 95% CI 1.86 to 4.09, p&lt;0.001). A diagnosis of hospital-acquired infection was more frequent in readmissions treated for pneumonia than other diagnoses (22.1% vs 3.9%, p&lt;0.001). Conclusion Pneumonia is the most common condition treated on readmission following hospitalisation with CAP and carries a higher mortality than both the index admission or readmission due to other diagnoses. Strategies to reduce readmissions due to pneumonia are required.
Targeting NEDD8-activating enzyme for cancer therapy: developments, clinical trials, challenges and future research directions
Authors: Dong-Jun Fu, Ting Wang
Journal: Journal of Hematology & Oncology (2023)

Abstract NEDDylation, a post-translational modification through three-step enzymatic cascades, plays crucial roles in the regulation of diverse biological processes. NEDD8-activating enzyme (NAE) as the only activation enzyme in the NEDDylation modification has become an attractive target to develop anticancer drugs. To date, numerous inhibitors or agonists targeting NAE have been developed. Among them, covalent NAE inhibitors such as MLN4924 and TAS4464 currently entered into clinical trials for cancer therapy, particularly for hematological tumors. This review explains the relationships between NEDDylation and cancers, structural characteristics of NAE and multistep mechanisms of NEDD8 activation by NAE. In addition, the potential approaches to discover NAE inhibitors and detailed pharmacological mechanisms of NAE inhibitors in the clinical stage are explored in depth. Importantly, we reasonably investigate the challenges of NAE inhibitors for cancer therapy and possible development directions of NAE-targeting drugs in the future.
Prognostic impact of secondary versus de novo ontogeny in acute myeloid leukemia is accounted for by the European LeukemiaNet 2022 risk classification
Authors: Michael J. Hochman, Megan Othus, Robert P. Hasserjian, Alex Ambinder, Andrew Brunner, Mary-Elizabeth M. Percival, Christopher S. Hourigan, Ronan Swords, Amy E. DeZern, Elihu H. Estey, Judith E. Karp
Journal: Leukemia (2023)

Abstract Secondary AML (sAML), defined by either history of antecedent hematologic disease (AHD) or prior genotoxic therapy (tAML), is classically regarded as having worse prognosis than de novo disease (dnAML). Clinicians may infer a new AML diagnosis is secondary based on a history of antecedent blood count (ABC) abnormalities in the absence of known prior AHD, but whether abnormal ABCs are associated with worse outcomes is unclear. Secondary-type mutations have recently been incorporated into the European LeukemiaNet (ELN) 2022 guidelines as adverse-risk features, raising the question of whether clinical descriptors of ontogeny (i.e., de novo or secondary) are prognostically significant when accounting for genetic risk by ELN 2022. In a large multicenter cohort of patients ( n = 734), we found that abnormal ABCs are not independently prognostic after adjusting for genetic characteristics in dnAML patients. Furthermore, history of AHD and tAML do not confer increased risk of death compared to dnAML on multivariate analysis, suggesting the prognostic impact of ontogeny is accounted for by disease genetics as stratified by ELN 2022 risk and TP53 mutation status. These findings emphasize the importance that disease genetics should play in risk stratification and clinical trial eligibility in AML.